This invention pertains to instrument systems and methods for positioning the body, or a portion of the body, of a surgical subject (or other xe2x80x9cbodyxe2x80x9d as defined herein) at a predetermined three-dimensional position in space. The systems and methods have especial utility for surgery, diagnostic intervention, and research involving the subject""s brain or other anatomical structure located in the interior of the subject""s body, wherein the brain or other anatomical structure has a buried locus of interest that normally is obscured by overlying structure.
In research and surgery of animals including small animals such as rats and mice, it can be extremely difficult to locate a terminus of a probe, electrode, micropipette, or other implement (herein generally termed a xe2x80x9cprobexe2x80x9d) at a particular location within the subject""s body without having to remove overlying structure and the like to permit direct observation of placement of the probe. This problem is especially critical in brain research involving the placement of a probe at a desired locus deep within a living subject""s brain inside the surrounding skull.
To aid researchers in locating various anatomical structures in the brains of research animals such as mice, rats, cats, dogs, and primates, respective so-called brain atlases are often consulted. A brain atlas provides three-dimensional coordinates for the structures, normally using a Cartesian (rectangular) coordinate system, relative to one or more accessible anatomical features. (For example, for mice and rats, the usual reference feature on the skull is bregma, which is a point of meeting of the coronal and sagittal sutures. A second reference feature that is sometimes used in connection with bregma is lambda, which is located posteriorly of bregma and is a point of meeting of the lambdoidal and sagittal sutures. The sagittal suture connecting bregma and lambda is regarded generally as representing a sagittal mid-line of the skull.) However, despite the existence of such information, current apparatus and methods used to place an introduced probe are notoriously inaccurate with individual subjects and from one subject to another in a population of subjects. Such inaccuracy is a substantial problem because it results in unintentionally mis-positioned probes and other tools, which causes misleading research data and wasted animal resources.
Stereotaxic apparatus are known in the art for positioning a subject""s head for brain research. For a small animal such as a mouse or rat, the head is held immobile by externally applied structures such as ear bars and a nose clamp providing a xe2x80x9cthree-pointxe2x80x9d holding system. As an example, reference is made to U.S. Pat. No. 5,601,570 to Altmann et al.
All known prior-art apparatus have various substantial shortcomings. For example, the Altmann et al. apparatus is inherently incapable of positioning a subject""s head, in three-dimensional space, in a manner providing a high level of confidence that a probe inserted from outside the skull will xe2x80x9chitxe2x80x9d a desired locus within the brain. More specifically, the Altmann et al. apparatus does not allow the researcher, intending to probe a living brain of a research animal, to position a particular animal""s head in a manner providing reliably accurate insertion and placement of the probe to desired three-dimensional coordinates in the brain. The Altmann apparatus also exhibits poor precision of placements of a probe at a desired locus in each animal in a population of animals. Consequently, the researcher must conduct a series of xe2x80x9cpilotxe2x80x9d studies, followed by histological confirmations, to compare actual probe results with desired results (e.g., to compare actual hit loci with desired hit loci based on information in a brain atlas). Such studies using conventional apparatus usually produce data exhibiting wide variations that often are attributed wrongly to biological variations among individual animals in a population, strains, ages of animals, and so on. As the pilot studies progress, the coordinates provided by a conventional apparatus are adjusted gradually to compensate for the variation and to improve the hit rate. Unfortunately, such studies are time-consuming and costly to perform, and require substantially increased numbers of animals to conduct a particular experiment. Conventional instruments simply do not allow the researcher to differentiate between the many sources of error. Furthermore, even with adjustments to the apparatus based on the pilot studies, hit rates remain disappointingly low, resulting in inconclusive research.
As noted above, individual animals (even of the same strain) exhibit substantial variation, one animal to the next, in morphology of body structures such as the skull. If positioning of the body or body structure is guided, according to the prior art, solely on the basis of external features (e.g., positions of ear holes relative to each other and to the snout), this variation usually results in excessive variation in probe placement at target loci within the brain.
In view of the shortcomings of the prior art summarized above, the present invention provides, inter alia, apparatus and methods for positioning the body, or portion of the body (such as the skull and its contents), of a research subject accurately in three-dimensional space. (As used herein, the term xe2x80x9cbodyxe2x80x9d can be an entire body such as an entire mouse or rat, or a portion of an entire body.) To achieve such positioning, the body is held in a holder configured to hold the body immobile in a desired position. The holder, in turn, is mounted in a manner allowing any of various motions in three-dimensional space required to achieve the desired positioning.
According to a first aspect of the invention, stereotaxic holders are provided for holding a body at a position in three-dimensional space. A representative embodiment of such a holder comprises a frame, an X-axis shift mechanism, a Y-axis shift mechanism, and a Z-axis shift mechanism (wherein the terms xe2x80x9cX-axis,xe2x80x9d xe2x80x9cY-axis,xe2x80x9d and xe2x80x9cZ-axisxe2x80x9d refer to the orthogonal axes in a Cartesian coordinate system. A body-holding component, configured to contact a body, can be attached to the frame such that the body-holding component extends from the frame to contact the body and hold the body relative to the frame. The frame is attached to the X-axis, Y-axis, and Z-axis shift mechanisms. The X-axis shift mechanism is configured to move the frame, with body-holding component, along an X-axis. The Y-axis shift mechanism is configured to move the frame, with body-holding component, along a Y-axis, wherein the movement along the Y-axis is independent of the movement along the X-axis. The Z-axis shift mechanism is configured to move the frame, with body-holding component, along a Z-axis, wherein the movement along the Z-axis is independent of the movement along the X-axis or along the Y-axis. The shift mechanisms are configured relative to each other so as to define a reference X-axis, a reference Y-axis, and a reference Z-axis, respectively, that are orthogonal relative to each other and that mutually intersect at a 0,0,0 point in three-dimensional space. The X-axis shift mechanism, Y-axis shift mechanism, and Z-axis shift mechanism are configured to move a body, mounted to the frame by the body-holding component, as required to place a selected point on or in the body at the 0,0,0 point.
The stereotaxic holder as summarized above can further comprise one or more of an X-axis tilting mechanism, a Y-axis tilting mechanism, and a Z-axis tilting mechanism. The X-axis tilting mechanism is configured to tilt a body, held by the frame, about the reference X-axis and relative to the 0,0,0 point. The Y-axis tilting mechanism is configured to tilt a body, held by the frame, about the reference Y-axis and relative to the 0,0,0 point. The Z-axis tilting mechanism is configured to tilt a body, held by the frame, about the reference Z-axis and relative to the 0,0,0 point. Each tilting motion is independent of any other tilting motion of the body or of any shifting motion of the frame as achieved by the stereotaxic holder.
The stereotaxic holder can further comprise at least one body-holding component attached to the frame. Exemplary body-holding components include, but are not limited to, ear bars and snout adapters.
In an example embodiment of a stereotaxic holder according to the invention, the frame is attached to the Z-axis shifting mechanism, the Z-axis shifting mechanism is attached to the X-axis shifting mechanism, and the X-axis shifting mechanism is attached to the Y-axis shifting mechanism. The example embodiment can further comprise a plate, wherein the X-axis tilting mechanism is attached to the plate. Hence, the Y-axis shifting mechanism is attached to the X-axis tilting mechanism, the Y-axis tilting mechanism is attached to the Y-axis shifting mechanism, the X-axis shifting mechanism is attached to the Y-axis tilting mechanism, and the Z-axis shifting mechanism is attached to the X-axis shifting mechanism. The plate can be mounted pivotably to a sub-plate to allow the plate to swing about the reference Z-axis. In such a configuration, the plate and sub-plate comprise the Z-axis tilting mechanism.
A second representative embodiment of a stereotaxic holder according to the invention comprises a first U-frame, a Z-axis shifting mechanism, an X-axis shifting mechanism, a Y-axis shifting mechanism, a Y-axis tilting mechanism, an X-axis tilting mechanism, and a Z-axis swing mechanism. A body-holding component, as summarized above, is attached to the first U-frame. The first U-frame is attached to the Z-axis shifting mechanism, which is configured to move the first U-frame, with body-holding component, along a Z-axis. The Z-axis shifting mechanism is attached to the X-axis shifting mechanism, which is configured to move the Z-axis shifting mechanism and first U-frame along an X-axis. The X-axis shifting mechanism is attached to the Y-axis shifting mechanism, which is configured to move the X-axis shifting mechanism, Z-axis shifting mechanism, and first U-frame along a Y-axis. The Y-axis tilting mechanism connects the X-axis shifting mechanism to the Y-axis shifting mechanism. The Y-axis tilting mechanism defines a reference Y-axis about which the Y-axis tilting mechanism effects tilting of the body. The Y-axis tilting mechanism is attached to the X-axis tilting mechanism, and the X-axis tilting mechanism is attached to the Z-axis swing mechanism. The X-axis tilting mechanism defines a reference X-axis about which the X-axis tilting mechanism effects tilting of the body, and the Z-axis swing mechanism defines a reference Z-axis about which the Z-axis swing mechanism effects a swing of the body. The reference X-axis, reference Y-axis, and reference Z-axis are orthogonal to each other and mutually intersect at a 0,0,0 point in three-dimensional space.
In the second representative embodiment as summarized above, the X-axis tilting mechanism can comprise a second U-frame having ends that pivot about the reference X-axis, and a base to which the Y-axis shifting mechanism is attached. In such a configuration, the Z-axis swing mechanism can comprise a plate and a sub-plate, wherein the X-axis tilting mechanism is attached to the plate and the plate is attached pivotably to the sub-plate to allow the plate to swing about the reference Z-axis.
According to another aspect of the invention, stereotaxic alignment systems are provided. A representative embodiment of such a system comprises a base plate and any of various stereotaxic holders according to the invention. For example, the stereotaxic holder can be configured as summarized above with respect to the first representative embodiment. In such a configuration, the stereotaxic holder can further comprise at least one of (desirably all three of) an X-axis tilting mechanism, a Y-axis tilting mechanism, and a Z-axis tilting mechanism. Each tilting mechanism, if present, is configured to tilt a body, held by the frame, about the respective reference axis and relative to the 0,0,0 point independently of any other tilting motion of the body or of any shifting motion of the frame.
In a stereotaxic alignment system according to the invention, the stereotaxic holder can include a centering gauge indicating the 0,0,0 point. For example, the centering gauge can be situated on the terminal face of a gauge post attached to the stereotaxic holder such that the gauge post is coaxial with the reference Z-axis.
Another representative embodiment of a stereotaxic alignment system according to the invention comprises a base plate, a stereotaxic holder (as summarized above) mounted to the base plate, and a manipulator mounted to the base plate. The manipulator includes a xe2x80x9ccontrolled endxe2x80x9d to which an implement can be mounted. Thus, the manipulator can present to the body a tool, held by the manipulator, at a desired locus on or in the body relative to the 0,0,0 point.
The manipulator desirably comprises an X-axis shifting mechanism, a Y-axis shifting mechanism, and a Z-axis shifting mechanism for shifting the controlled end along an X-axis, Y-axis, and Z-axis, respectively, relative to the 0,0,0 point. The manipulator further comprises a three-axis universal joint to which the X-axis shifting mechanism, the Y-axis shifting mechanism, and Z-axis shifting mechanism are mounted. The universal joint desirably is configured to allow adjustment of an orthogonal relationship of the X-axis, Y-axis, and Z-axis of the manipulator relative to each other. The universal joint can be configured further to allow adjustment of one or more of the X-axis, Y-axis, and Z-axis of the manipulator with one or more of the reference X-axis, reference Y-axis, and reference Z-axis of the stereotaxic holder.
In a stereotaxic alignment system according to the invention, the manipulator can include an implement mounted to the controlled end of the manipulator. Desirably, any of various implements has an alignment axis (usually the longitudinal axis of the implement). Desirably, any implement attachable to the controlled end is xe2x80x9cself-indexingxe2x80x9d as defined herein.
An exemplary implement is a centering scope usable with a centering gauge, as summarized above, that indicates the 0,0,0 point. The centering scope has an optical axis that is coincident with the alignment axis. In such an arrangement, the manipulator is configured to position the centering scope in an adjustable manner such that the optical axis intersects the centering gauge at the 0,0,0 point.
Other exemplary implements include, but are not limited to, drilling units, syringe holders, dial test indicators, cannula-insertion devices, and a stereotaxic alignment indicators.
According to another aspect of the invention, methods are provided for performing a stereotaxic alignment of a body. According to a representative embodiment of such a method, a reference X-axis, a reference Y-axis, and a reference Z-axis are provided that are orthogonal to each other and that mutually intersect at a 0,0,0 point in three-dimensional space. The body is mounted in a holder configured to effect respective controlled shifts of the body in an X-axis direction, a Y-axis direction, and a Z-axis direction, and to effect respective controlled tilts of the body about the reference X-axis and reference Y-axis, as well as controlled swings of the body about the reference Z-axis. Using the holder, the body is shifted as required in the X-axis, Y-axis, and Z-axis dimensions to place a selected target point on or in the body at the 0,0,0 point. Further using the holder, the body is subjected to a swinging motion as required about the reference Z-axis while maintaining the target point at the 0,0,0 point, to obtain a desired orientation of the body relative to the reference Y-axis or the reference X-axis. Further using the holder, the body is tilted as required about the reference Y-axis while maintaining the target point at the 0,0,0 point, so as to obtain a desired orientation of the body relative to the reference X-axis. Further using the holder, the body is tilted as required about the reference X-axis while maintaining the target point at the 0,0,0 point, so as to obtain a desired orientation of the body relative to the reference Y-axis. The step of swinging the body about the reference Z-axis can comprise the steps of: (1) identifying a first reference point and a second reference point on or in the body, wherein the first and second reference points define a reference line; and (2) swinging the body as required about the reference Z-axis until the reference line is at a desired orientation relative to the reference X-axis or the reference Y-axis. The reference line can be, for example, a sagittal axis of the body, wherein placing the reference line at the desired orientation achieves a sagittal alignment of the body.
The step of tilting the body about the reference Y-axis can comprise the steps of: (1) providing a stereotaxic alignment indicator for ascertaining the orientation of the body relative to the reference X-axis; (2) placing the stereotaxic alignment indicator into functional contact with the body; and (3) tilting the body as required until the stereotaxic alignment indicator indicates the desired orientation of the body about the reference Y-axis relative to the reference X-axis. For example, the body can be aligned to have its sagittal axis aligned with the reference Y-axis, wherein obtaining the desired orientation of the body about the reference Y-axis places the body at a desired coronal tilt.
The step of tilting the body about the reference X-axis can comprise the steps of: (1) providing a stereotaxic alignment indicator for ascertaining the orientation of the body relative to the reference Y-axis; (2) placing the stereotaxic alignment indicator into functional contact with the body; and (3) tilting the body as required until the stereotaxic alignment indicator indicates the desired orientation of the body about the reference X-axis relative to the reference Y-axis. For example, the body can be aligned to have its sagittal axis aligned with the reference Y-axis, wherein obtaining the desired orientation of the body about the reference X-axis places the body at a desired dorsal tilt.